The Effect Of Masculinizing Hormone Therapy On Wound Healing In Sterilized Mice
Erik Reiche, MD1,2, Patrick R. Keller, MD1, Yu Tan, PHD2, Matthew Louis, MD1, Vance Soares, MD2, Devin Coon, MD1,3.
1Department of Plastic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Department of Biomedical Engineering, Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3Division of Plastic Surgery, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
PURPOSE: Wound healing is a topic of great interest in plastic surgery. Prior work has demonstrated sex-dependent differences in wound healing, but mechanisms underpinning these differences are poorly understood. There is general agreement among experts that transgender men on masculinizing hormone therapy heal wounds worse than those who arenít. The morbidity of this poor wound healing is high and includes problems such as unsightly hypertrophic scars and urethral stenosis. It is known that androgens are associated with an increased local inflammatory response, decreased collagen matrix deposition, and delayed cutaneous wound healing. To further understand this phenomenon, we designed a novel mouse model and studied the effects of trans-sex hormones on wound healing in castrated mice.
METHODS: CB57BL/6J mice were randomized to 6 groups based on gender, hormone regimen and surgical castration (total n = 75). Ovariectomies, gonadectomies or sham occurred on day 0 and mice were assigned to receive either no-, mono-, or bi-weekly exogenous testosterone for 3 weeks. Bilateral dorsal excisional wounding (6mm punch biopsy) occurred on day 14, and wound were stented open with plastic 6mm rings (secured with suture) to ensure healing via reepithelization as opposed to contraction (Figure 1). Wounds were harvested on day 21 and assessed for planimetry, histology (H&E, trichrome), immunofluorescence, and qPCR (TNFα). Serum testosterone levels were obtained with mass spectrometry. All protocols were approved by Johns Hopkins ACUC. Difference in means was tested with one-way ANOVA with significance set at 0.05.
RESULTS: There was a statistically significant difference in mean normalized TNFα concentrations between the six groups (F = 2.50, F critic = 2.35, P = 0.039). Wound sample TNFα concentration was highest in female mice that were on exogenous testosterone (Figure 2). Wound histologic analysis showed poorer wound healing (decreased re-epithelization, larger wound size, increased granulation tissue) in female mice that received exogenous testosterone versus female groups that did not (Figure 3).
CONCLUSION: Preliminary results in our novel murine transgender wound healing model suggest that testosterone increases inflammation and impairs wound healing with significantly more detrimental effects in XX as compared to XY mice, even with identical hormone levels. These effects may be in part mediated by TNFα activity. Ongoing work is focused on characterizing the hormone-mediated effects of TNFα in wound healing in transgender models and developing topical therapeutic interventions.
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